Variant 1-179088088-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000367627.8(TOR3A):c.817A>C(p.Ser273Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000085 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TOR3A
ENST00000367627.8 missense, splice_region

Scores

Splicing: ADA: 0.9993

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.91

Variant links:

Genes affected

TOR3A (HGNC:11997): (torsin family 3 member A) Predicted to enable ATP binding activity. Located in endoplasmic reticulum lumen. [provided by Alliance of Genome Resources, Apr 2022]

TOR3A links:

TOR3A (HGNC:):

TOR3A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR3A	NM_022371.4 linkuse as main transcript	c.817A>C	p.Ser273Arg	missense_variant, splice_region_variant	4/6	ENST00000367627.8	NP_071766.2	Q9H497-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR3A	ENST00000367627.8 linkuse as main transcript	c.817A>C	p.Ser273Arg	missense_variant, splice_region_variant	4/6	1	NM_022371.4	ENSP00000356599.3		Q9H497-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000846

AC:

121

AN:

1430224

Hom.:

Cov.:

AF XY:

0.0000887

AC XY:

AN XY:

710474

show subpopulations

Gnomad4 AFR exome

AF:

0.0000935

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000771

Gnomad4 SAS exome

AF:

0.0000731

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000966

Gnomad4 OTH exome

AF:

0.0000510

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.817A>C (p.S273R) alteration is located in exon 4 (coding exon 4) of the TOR3A gene. This alteration results from a A to C substitution at nucleotide position 817, causing the serine (S) at amino acid position 273 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Benign

-0.77

MutationAssessor

Pathogenic

3.3

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.020

D;D;D

Polyphen

0.89

P;.;.

Vest4

0.98

MutPred

0.92

Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);.;

MVP

0.76

MPC

0.72

ClinPred

1.0

GERP RS

5.3

Varity_R

0.86

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over